Autoimmune Inflammatory Disease Research Articles

Early involvement of peripherally derived monocytes in inflammation in an NMO-like mouse model

Neuromyelitis optica (NMO) is an autoimmune inflammatory disease that primarily affects the optic nerve and spinal cord within the central nervous system (CNS). Acute astrocyte injury caused by autoantibodies against aquaporin 4 (NMO-IgG) is a well-established key factor in the pathogenesis, ultimately leading to neuronal damage and patient disability. In addition to these humoral immune processes, numerous innate immune cells were found in the acute lesions of NMO patients. However, the origin and function of these innate immune cells remain unclear in NMO pathogenesis. Therefore, this study aims to analyze the origin and functions of these innate immune cells in an NMO-like mouse model and evaluate their role in the pathophysiology of NMO. The expression of Tmem119 on Iba1 + cells in brain tissue disappeared immediately after the injection of NMO-IgG + human complement mixture, while the expression of P2ry12 remained well-maintained at 1 day after injection. Based on these observations, it was demonstrated that monocytes infiltrate the brain during the early stages of the pathological process and are closely associated with the inflammatory response through the expression of the proinflammatory cytokine IL-1β. Understanding the variations in the expression patterns of P2ry12, Tmem119, and other markers could be helpful in distinguishing between these cell types and further analyzing their functions. Therefore, this research may contribute to a better understanding of the mechanisms and potential treatments for NMO.

Demographic, Clinical Profile of Rheumatoid Arthritis Patients and Their Association with Disease Severity in Ghana.

Rheumatoid arthritis (RA) is one of the frequent chronic, systemic, inflammatory autoimmune disorders with an estimated global prevalence of 1%. RA leads to joint destruction and disability if left untreated. Ghana has seen very few studies on RA, and little is known about the disease's severity and related variables. This study sought to characterize the clinical presentation and determine disease severity and associated risk factors with disease severity among RA patients in a tertiary hospital in Ghana. This cross-sectional study was conducted between September 2020 and August 2021. This study included 56 consecutively consenting RA patients from the Komfo Anokye Teaching Hospital orthopaedic unit. Diagnosis of RA was based on the updated American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2022 rheumatoid arthritis classification criteria by a rheumatologist. A study questionnaire was used to gather participant demographics and clinical features, and results from the laboratory were taken from the patients' charts and medical records. The patients' disease severity was evaluated based on the rheumatoid arthritis disease activity score, which is based on a 28-joint count (DAS28), and their functioning was evaluated using the modified health assessment questionnaire. The participants' mean age was 51.25 ± 13.22 years. Out of the total participants, 46 were females, and 10 were males (female-to-male ratio 4.6 : 1). Moreover, 37.50% had arthritis of the hand; 5.30% had severe disease, and 94.60% were not severe. A majority (76.80%) were on methotrexate medication. The most frequently involved joints were the knee (42.90%), wrist (32.10%), and elbow (12.50%). There was no statistically significant association with disease severity and a functional status score of >0.5 (cOR: 10.60, 95% CI (0.52-217.30); p = 0.124). In addition, marital status (p = 0.04), disease duration (p = 0.04), family complaints (p = 0.02), and ESR (p = 0.03) were significantly associated with disease severity. RA is predominant among elder populations and females. Disease duration, family complaints, and ESR are associated with disease severity. The findings of this study call for interventions towards ensuring early diagnosis of RA among high-risk populations to enhance good management practices.

Investigation of pyroptosis-related hub genes and the immune microenvironment in primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is an inflammatory systemic autoimmune disease, while the role and mechanisms of pyroptosis in pSS remain largely undefined. Pyroptosis-related genes and gene expression data were obtained from the Molecular Signatures Database and NCBI GEO databases. Differentially expressed genes (DEGs) and pyroptosis-related hub genes were identified by R software. Functional enrichment analyses were conducted using the "ClusterProfiler" R package and WebGestalt7. CIBERSORTx was used to calculate the correlations between immune cells and pyroptosis. Subsequently, histological staining was performed on salivary gland samples from non-pSS and pSS patients to identify the expression of pyroptosis-related genes. Immunofluorescence double staining was conducted to validate the correlation between immune cells and pyroptosis. A total of 1494 DEGs were identified between eight pSS samples and 10 healthy volunteer samples. Five pyroptosis-related hub genes (AIM2, CASP1, CASP3, IL6, TNF) were recognised. DEGs were mostly enriched in immunity-related terms and several immune cells were associated with the hub genes in pSS. Among them, delta gamma T cell was significantly positively correlated with CASP3. Finally, the protein levels of these hub genes were validated to be elevated in the labial minor salivary gland biopsies of pSS patients compared to those of healthy volunteers using immunohistochemical staining. Immunofluorescence double staining further showed that IL-6, AIM2, CASP1and CASP3 were related to delta gamma T cells, and TNF was related to dendritic cells. This study uncovered a significant interaction between pyroptosis and the immune microenvironment in pSS patients. Besides, we identified five pyroptosis-related hub genes that might play a role in the pathogenesis of pSS. These findings could offer valuable insights for the development of novel treatment strategies for pSS.

Current pharmacological therapy for rheumatoid arthritis, factors for its effectiveness and associated complications: systematic review

Rheumatoid arthritis (RA) is a chronic, autoimmune, and systemic inflammatory disease that mainly affects diarthrodial joints. Its global prevalence is 0,5-1 % in adults, increasing to 5 % in women over 55 years old. RA reduces the quality of life and life expectancy by 3-10 years, mainly due to associated cardiovascular diseases. Current treatment is based on initiating early disease-modifying therapy with the goal of suppressing inflammation, inducing remission, preventing joint damage, and improving functionality. Antirheumatic medications include non-steroidal anti-inflammatory drugs, glucocorticoids, non-biological immunosuppressants like methotrexate, and biological immunomodulators such as anti-TNF or anti-interleukins, which have shown high clinical effectiveness. However, there is individual variability in therapeutic response, adverse effects, and loss of efficacy over time. This study conducted a systematic literature review following the PRISMA methodology. The search was performed on PubMed, Scopus, and Web of Science, using MESH terms and keywords related to rheumatoid arthritis, treatments, effectiveness, and prognostic factors. Studies published between 2015-2022 were included, ultimately selecting 30 articles that met eligibility criteria. The objective of this review was to compile and synthesize available evidence on currently used medications and therapies for rheumatoid arthritis, factors associated with therapeutic success, and the most frequently reported complications or adverse effects. The results contribute to enhancing treatment strategies, considering a personalized approach based on each patient's needs.

Myeloid-specific deletion of group VIA calcium-independent phospholipase A2 induces pro-inflammatory LPS response predominantly in male mice via MIP-1α activation

Polymorphisms of group VIA calcium-independent phospholipase A2 (PLA2G6) are associated with blood C-reactive protein suggesting its role in inflammation. We showed that myeloid-specific Pla2g6-deficiency in Pla2g6M−/− mice led to exaggerated inflammation and fibrosis in a lean fatty liver model. We here investigated whether these mutants display alteration in immune response after treatment with E. coli lipopolysaccharides (LPS) under acute (a single dose) and persistent (four doses) conditions. Without LPS treatment, male Pla2g6M−/− (but not Flox) mice at 12 months of age exhibited splenomegaly and hepatic necrosis, and ~ 30 % of them exhibited autoimmune hepatitis showing lymphoplasma cells with CD3(+) and CD45R(+) staining. Under acute LPS, male mutants showed an elevation of plasma MIP-1α and immunoglobulinA as well as upregulation of hepatic apoptosis and fibrosis PARP-1, Bax, MCP-1, α-SMA, and collagen I proteins. Their bone-marrow-derived macrophages also showed an elevation of MIP-1α release upon LPS stimulation in vitro. Female mutants under acute LPS showed a moderate increase in plasma KC/CXCL1, MCP-1, and IL10, and they showed no remarkable increase in hepatic fibrosis under acute or persistent LPS. Male mutants under persistent LPS displayed an elevation of aspartate aminotransferase, blood eosinophils, and hepatic apoptosis. Moreover, ~30 % of these mutants exhibited eosinophilic sclerosing portal hepatitis associated with an upregulated protein expression of hepatic CD8α, CD68, eosinophilic cationic protein, and Ly6G. Thus, myeloid-PLA2G6 deficiency led to an autoimmune and LPS-induced inflammatory liver disease via MIP-1α in a male-predominant manner. Our results may be applicable to patients with PLA2G6 mutations who undergo bacterial infection and sepsis.

Mechanisms Governing Oligodendrocyte Viability in Multiple Sclerosis and Its Animal Models.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disease of the central nervous system (CNS), which is triggered by an autoimmune assault targeting oligodendrocytes and myelin. Recent research indicates that the demise of oligodendrocytes due to an autoimmune attack contributes significantly to the pathogenesis of MS and its animal model experimental autoimmune encephalomyelitis (EAE). A key challenge in MS research lies in comprehending the mechanisms governing oligodendrocyte viability and devising therapeutic approaches to enhance oligodendrocyte survival. Here, we provide an overview of recent findings that highlight the contributions of oligodendrocyte death to the development of MS and EAE and summarize the current literature on the mechanisms governing oligodendrocyte viability in these diseases.

An ADAM10 Exosite Inhibitor Is Efficacious in an In Vivo Collagen-Induced Arthritis Model.

Rheumatoid arthritis is a systemic autoimmune inflammatory disease that affects millions of people worldwide. There are multiple disease-modifying anti-rheumatic drugs available; however, many patients do not respond to any treatment. A disintegrin and metalloproteinase 10 has been suggested as a potential new target for RA due to its role in the release of multiple pro- and anti-inflammatory factors from cell surfaces. In the present study, we determined the pharmacokinetic parameters and in vivo efficacy of a compound CID3117694 from a novel class of non-zinc-binding inhibitors. Oral bioavailability was demonstrated in the blood and synovial fluid after a 10 mg/kg dose. To test efficacy, we established the collagen-induced arthritis model in mice. CID3117694 was administered orally at 10, 30, and 50 mg/kg/day for 28 days. CID3117694 was able to dose-dependently improve the disease score, decrease RA markers in the blood, and decrease signs of inflammation, hyperplasia, pannus formation, and cartilage erosion in the affected joints compared to the untreated control. Additionally, mice treated with CID 3117694 did not exhibit any clinical signs of distress, suggesting low toxicity. The results of this study suggest that the inhibition of ADAM10 exosite can be a viable therapeutic approach to RA.

Biological and glucocorticoids treatment impair the medium-term immunogenicity to SARS-CoV-2 mRNA vaccines in autoimmune inflammatory rheumatic diseases

BackgroundThis study aims to assess the sustained immunological response to the SARS-CoV-2 vaccine in patients with autoimmune inflammatory rheumatic diseases (AIRD) undergoing different treatment regimens.MethodsWe conducted a prospective observational study involving 157 AIRD patients without prior COVID-19 infection. Treatment regimens included non-treatment or glucocorticoid-only (not-treated/GCs), non-biological drugs, biological therapy, and JAK inhibitors. All participants completed the two-dose vaccine schedule, and 110 of them received an additional booster dose. Serum samples were collected approximately 3–6 months after the second and third vaccine doses to measure antibodies against the Spike protein (antiS-AB) and neutralizing antibodies (nAB) targeting six SARS-CoV-2 variants.ResultsFollowing the third dose, all patients exhibited a significant increase in antiS-AB (FC = 15, p < 0.0001). Patients under biological therapy had lower titres compared to the non-biological (66% decrease, p = 0.038) and the not-treated/GCs group (62% decrease, p = 0.0132), with the latter persisting after the booster dose (86% decrease, p = 0.0027). GC use was associated with lower antiS-AB levels in the biological group (87% decrease, p = 0.0124), although not statistically significant after confounders adjustment. nABs showed the highest positivity rates for the wild-type strain before (50%) and after the booster dose (93%), while the Omicron variant exhibited the lowest rates (11% and 55%, respectively). All variants demonstrated similar positivity patterns and good concordance with antiS-AB (AUCs from 0.896 to 0.997).ConclusionsThe SARS-CoV-2 vaccine booster strategy effectively elicited a sustained antibody immune response in AIRD patients. However, patients under biological therapies exhibited a reduced response to the booster dose, particularly when combined with GCs.

Immune cells in the epithelial immune microenvironment of psoriasis: emerging therapeutic targets.

Psoriasis is a chronic autoimmune inflammatory disease characterized by erroneous metabolism of keratinocytes. The development of psoriasis is closely related to abnormal activation and disorders of the immune system. Dysregulated skin protective mechanisms can activate inflammatory pathways within the epithelial immune microenvironment (EIME), leading to the development of autoimmune-related and inflammatory skin diseases. In this review, we initially emphasized the pathogenesis of psoriasis, paying particular attention to the interactions between the abnormal activation of immune cells and the production of cytokines in psoriasis. Subsequently, we delved into the significance of the interactions between EIME and immune cells in the emergence of psoriasis. A thorough understanding of these immune processes is crucial to the development of targeted therapies for psoriasis. Finally, we discussed the potential novel targeted therapies aimed at modulating the EIME in psoriasis. This comprehensive examination sheds light on the intricate underlying immune mechanisms and provides insights into potential therapeutic avenues of immune-mediated inflammatory diseases.

Design and validation of a Questionnaire on the factors influencing self-care behaviors in patients with Multiple sclerosis (QFASMS)

BackgroundMultiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS). Since MS does not have a definitive cure, individuals affected by it need to adapt and coordinate with their chronic illness in order to fulfill their duties and responsibilities. The first step in helping patients to better care for and manage their illness is to engage in self-care behaviors. This study was conducted with the aim of design and validation of a questionnaire on the factors influencing self-care behaviors in patients with Multiple sclerosis.MethodsThis cross-sectional study was conducted on Multiple sclerosis patients in Iran in 2023. The age range of patients varied between 22 and 52 years. Having MS disease, passing one year of the disease duration, living in Mashhad city, having informed consent to participate in the study and not completing the questionnaire were the entry and exit criteria of the study.ResultsThis study was conducted on 500 patients with multiple sclerosis. Based on the results of psychometrics (face, content and construct validity), the number of questions was reduced from 120 to 47 questions and 73 questions were eliminated. Finally, the questionnaire was approved with 47 questions and 4 subscales of understanding the symptoms of the disease (9 questions), tendency to conscious and targeted care (21 questions), laziness in care (8 questions) and tendency to receive therapy services (9 questions). Cronbach's alpha and McDonald's omega index for all questionnaire questions were 0.877 and 0.881, respectively.ConclusionsBased on the results of this questionnaire, 47 questions and 4 subscales can be used to measure the factors influencing the adoption of self-care behaviour’s in patients with multiple sclerosis.

The NLRP3 Inflammasome as a Pathogenic Player Showing Therapeutic Potential in Rheumatoid Arthritis and Its Comorbidities: A Narrative Review.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by chronic synovitis and the progressive destruction of cartilage and bone. RA is commonly accompanied by extra-articular comorbidities. The pathogenesis of RA and its comorbidities is complex and not completely elucidated. The assembly of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activates caspase-1, which induces the maturation of interleukin (IL)-1β and IL-18 and leads to the cleavage of gasdermin D with promoting pyroptosis. Accumulative evidence indicates the pathogenic role of NLRP3 inflammasome signaling in RA and its comorbidities, including atherosclerotic cardiovascular disease, osteoporosis, and interstitial lung diseases. Although the available therapeutic agents are effective for RA treatment, their high cost and increased infection rate are causes for concern. Recent evidence revealed the components of the NLRP3 inflammasome as potential therapeutic targets in RA and its comorbidities. In this review, we searched the MEDLINE database using the PubMed interface and reviewed English-language literature on the NLRP3 inflammasome in RA and its comorbidities from 2000 to 2023. The current evidence reveals that the NLRP3 inflammasome contributes to the pathogenesis of RA and its comorbidities. Consequently, the components of the NLRP3 inflammasome signaling pathway represent promising therapeutic targets, and ongoing research might lead to the development of new, effective treatments for RA and its comorbidities.

Design and development of an herbal anti-arthritic gel incorporating Alstonia scholaris latex

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease leading to bone and joint damage. The current study reports the development of an herbal anti-arthritic gel formulation incorporating the latex of Alstonia scholaris (AS). Six batches of topical herbal gels (G1-G6) were formulated by dispersion method using different concentrations of AS latex (0.5 % to 3.0 % w/w) in Carbopol 934 (1.5% w/w) gel base. The gels were evaluated for various physicochemical properties using standard methods and G4 was selected as an optimized formulation based on the desirable properties of a topical gel. The in vivo anti-arthritic potential of G4 was evaluated using a complete Freund’s adjuvant (CFA)-induced arthritic rat (Sprague Dawley) model for 28 days. Assessment of various arthritic parameters including hematological and biochemical parameters and radiography of hind legs in arthritic rats was carried out. The developed herbal gels were found to be uniform and stable. The G4 gel formulation showed a maximum drug release of 95.22% following Higuchi kinetic model. The topical application of G4 gel exhibited significant (p<0.05) anti-arthritic activity compared to diseased rats. The herbal gel G4 effectively restored the arthritic, hematological and biochemical parameters in arthritic rats. Radiographic analysis demonstrated its ability to reduce soft tissue swelling and thus prevented bone degeneration and the narrowing of joint spaces. These results supported that the developed herbal gel may offer a novel therapeutic approach in the treatment of RA with fewer side effects, good patient compliance, high efficacy, and low cost.

Evaluating microRNA-499 expression and serum IL-17, ACCP and PADI4 cytokine levels in rheumatoid arthritis patients undergoing anti-TNF alpha therapy

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by joint inflammation and damage. While anti-TNF-alpha therapies like infliximab have revolutionized RA, treatment response varies among patients. Identifying reliable biomarkers for treatment response is crucial for optimizing therapy and patient outcomes. MicroRNA-499 has been implicated in autoimmune diseases, and IL-17 is a key mediator in RA pathogenesis. Additionally, PADI4 and ACCP are linked to RA autoimmunity. This study aimed to investigate the potential of microRNA-499 expression, serum levels of IL-17, PADI4 and ACCP as biomarkers for predicting and monitoring treatment response in RA patients undergoing anti-TNF-alpha (infliximab) therapy. Methodology: In this case-control research, blood samples from 100 Iraqi patients with RA and 100 controls were collected. RNA was extracted and the levels of miRNA499 were quantified using real-time PCR. The serum IL-17, PADI4 and ACCP levels were determined using ELISA. Patients were sub-grouped as responders and non-responders based on their responses to anti-TNF-alpha (infliximab) treatment. Results: The mean age of the patients in this study was 46.22 years. The occurrence of RA was higher in age group (31-45) years. There was a significant association between RA, smoking and BMI. miRNA-499 expression was significantly higher in RA patients versus controls (1.1 folds in patients compared to 0.52 in control group). The serum levels of IL-17, PADI4 and ACCP was significantly higher in RA patients than controls (54.3ng/L, 2.52 ng/ml and 2.15 U/ml) vs (40.35ng/ L, 1.78 ng/ml and 1.06 U/ml) respectively. Subdividing of patients showed that miRNA-499 expression and serum IL-17, PADI4 and ACCP to be significantly higher in non-responders patients than responders. Conclusion: MicroRNA-499 expression, serum levels of IL-17, PADI4 and ACCP were found to be significantly higher in RA patients compared to control group as well as in non-responding than responding patients.

Autoimmunity-related LINC01934 and AP002954.4 lncRNA polymorphisms may be effective in pediatric celiac disease: a case-control study.

Various studies have reported that certain long non-coding RNA levels are unusually low in the intestines of celiac disease patients, suggesting that this may be associated with the inflammation observed in celiac disease. Despite these studies, the research aimed at uncovering the potential role of long non-coding RNAs in the pathogenesis of autoimmune diseases like celiac disease remains insufficient. Therefore, in this study, we plan to assess long non-coding RNA polymorphisms associated with autoimmunity in children diagnosed with celiac disease according to the European Society for Paediatric Gastroenterology Hepatology and Nutrition criteria. DNA was isolated from paraffin tissue samples of 88 pediatric celiac disease patients and 74 healthy pediatric individuals. Single-nucleotide polymorphism genotyping of five long non-coding RNA polymorphisms associated with autoimmunity (LINC01934-rs1018326, IL18RAP-rs917997, AP002954.4-rs10892258, UQCRC2P1-rs6441961, and HCG14 rs3135316) was conducted using the TaqMan single-nucleotide polymorphism genotyping assays with the LightCycler 480. In our study, the genotypic and allelic frequency distribution of LINC01934-rs1018326 and AP002954.4-rs10892258 polymorphisms was found to be statistically significant in the comparison between the two groups (p<0.05). According to the multiple genetic model analyses, the LINC01934-rs1018326 polymorphism was observed to confer a 1.14-fold risk in the recessive model and a 1.2-fold risk in the additive model for pediatric celiac disease. Similarly, the AP002954.4-rs10892258 polymorphism was found to pose a 1.40-fold risk in the dominant model and a 1.7-fold risk in the additive model. Our study results draw attention to the LINC01934-rs1018326 and AP002954.4-rs10892258 polymorphisms in celiac disease and suggest that these polymorphisms may be associated with inflammation in autoimmune diseases like celiac disease.

Euthymic despite pain: the role of cognitive reappraisal and experiential avoidance in autoimmune inflammatory rheumatic diseases-a cross-sectional study.

Pain is a central feature of inflammatory rheumatic diseases and is associated with psychological distress. Pain is widely recognized not as a mere physical sensation, but as a complex, multidimensional phenomenon with an affective component. A plethora of research has conceptualized adaptation to pain by focusing on minimizing the pain experience. However, pain in autoimmune inflammatory rheumatic diseases is often neither avoidable nor curable. This cross-sectional study aimed to investigate the processes explaining how pain intensity may be associated with low well-being and why some patients may live well despite pain. Drawing upon the psychological (in)flexibility model and the process model of emotion regulation, we propose that cognitive reappraisal moderates the association between pain and euthymia through experiential avoidance. Ninety-seven patients with rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis were included for analyses (mean age = 53.4; mean time since diagnosis = 9.2 years). Most patients were women (75%), married/cohabitant (71%), and attended high school (47%). Results indicate that experiential avoidance may explain how severe pain is associated with lowered euthymia. This indirect negative effect of pain intensity on euthymia became non-significant at high levels of cognitive reappraisal, suggesting that cognitive reappraisal may serve as a protective factor for patients with autoimmune inflammatory rheumatic diseases. This study paves the way for future research in this promising context by providing an initial step towards integrating emotion regulation and psychological inflexibility in pain conditions.

A review on cytomegalovirus in patients with autoimmune inflammatory rheumatic diseases: Prevalence, clinical spectrum, treatment, and antiviral prophylaxis

Human cytomegalovirus (CMV) is a highly infectious virus that is prevalent among adults worldwide. In immunocompetent individuals, CMV infection rarely causes complications. Following initial infection, however, CMV remains latent in the body and can be reactivated especially in immunocompromised patients, such as those with autoimmune inflammatory rheumatic diseases (AIIRDs), leading to tissue-invasive, life-threatening diseases, such as colitis, vascular thrombosis, and pneumonitis. Although there are standard treatment recommendations for symptomatic CMV disease, there is paucity of consensus in the role of primary and secondary antiviral prophylaxis to prevent CMV reactivation, especially in AIIRDs patients undergoing immunosuppressive therapy. Therein, this review aimed to provide an overview of the prevalence, clinical disease, risk factors, and treatment for CMV infection, as well as on the role of primary and secondary antiviral prophylaxis in AIIRDs patients. The emerging novel techniques that measure CMV-specific T-cell immunity as a guide to initiate prophylaxis in high-risk patients were also discussed.

Tofacitinib and peficitinib inhibitors of Janus kinase for autoimmune disease treatment: a quantum biochemistry approach.

Autoimmune inflammatory diseases, such as rheumatoid arthritis (RA) and ulcerative colitis, are associated with an uncontrolled production of cytokines leading to the pronounced inflammatory response of these disorders. Their therapy is currently focused on the inhibition of cytokine receptors, such as the Janus kinase (JAK) protein family. Tofacitinib and peficitinib are JAK inhibitors that have been recently approved to treat rheumatoid arthritis. In this study, an in-depth analysis was carried out through quantum biochemistry to understand the interactions involved in the complexes formed by JAK1 and tofacitinib or peficitinib. Computational analyses provided new insights into the binding mechanisms between tofacitinib or peficitinib and JAK1. The essential amino acid residues that support the complex are also identified and reported. Additionally, we report new interactions, such as van der Waals; hydrogen bonds; and alkyl, pi-alkyl, and pi-sulfur forces, that stabilize the complexes. The computational results revealed that peficitinib presents a similar affinity to JAK1 compared to tofacitinib based on their interaction energies.

Urinary tissue factor (uTF), tissue factor pathway inhibitor (TFPI) and plasmin as novel biomarkers in early diagnosis of lupus nephritis

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease, with multi systematic affection. Lupus nephritis (LN) is the most frequent cause of renal damage in SLE patients with variable presentations that may progress to end stage renal failure. Coagulation disorders are frequently reported in SLE and LN with higher mortality rates. Renal biopsy is an invasive process, and the existing indicators for LN diagnosis and activity are unreliable. New urinary biomarkers with significant validity, safety, and accuracy are the current focus of most studies. Our study sought to assess the value of urinary tissue factor (uTF), tissue factor pathway inhibitor (TFPI), and plasmin as biomarkers for the early identification and detection of LN and its activity. This was a cross-sectional study, included 100 subjects (80 SLE patients, and 20 healthy controls), they were recruited from the Internal Medicine department, Rheumatology and Nephrology units and outpatient’s clinics at Assiut University hospital between the period of 2020 and 2022. All patients underwent full history taking, clinical evaluation, and activity scoring calculation and laboratory investigations. The results showed that the best diagnostic accuracy of LN was observed with TFPI (90% accuracy, sensitivity 80% and specificity 95% with p&lt;0.001 at cutoff point of &gt;193.2 ng/ml), followed by uTF (75.4% overall accuracy at cut off point of &gt;12.6 ng/ml, sensitivity 90% and specificity 68% with p&lt; 0.001) and plasmin (70.3% accuracy at cut off point of &gt;30.5 ng/ml, sensitivity 55% and specificity 78% with p&lt; 0.001). Urinary TFPI was the best predictor of LN occurrence with odd ratio of 4.34, (p&lt; 0.001). In conclusion urinary TFPI could be used as a diagnostic marker for LN with high accuracy and an early predictor of LN.

Phlorizin Regulates Synovial Hyperplasia and Inflammation in Rats With Rheumatoid Arthritis by Regulating the mTOR Pathway.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease, and management of it is still a challenge. The present investigation assessed the potential preventive effect of phlorizin on rats with RA. A total of 40 healthy Wistar rats were used for this study. Bovine type II collagen and Freund's incomplete adjuvant (1:1 and 1 mg/ml) were administered on days 1 and 8 of the protocol to induce RA in rats; treatment with phlorizin at 60 or 120 mg/kg was started after the 4th week of the protocol, and its effect on inflammation, level of inflammatory cytokines, and expression of proteins were estimated in RA rats. Moreover, an in vitro study was performed on fibroblast-like synoviocytes (FLSs), and the effects of phlorizin on proliferation, apoptosis, and expression of the mechanistic target of rapamycin kinase pathway protein after stimulating these cells with tumor necrosis factor α (TNF-α) were estimated. The data obtained from the study indicate that phlorizin has the potential to mitigate inflammation and enhance weight management in rats with RA induced by bovine type II collagen (CII). The level of inflammatory cytokines in the serum and the expression of protein kinase B (AKT), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and mechanistic target of rapamycin kinase (mTOR) proteins in the joint tissue were reduced in phlorizin-treated rats with RA. In this investigation, phlorizin was shown to reverse the histological abnormalities in the joint tissue of rats with RA. The in-vitro study showed that phlorizin reduced proliferation and had no apoptotic effect on TNF-α-stimulated FLSs. Expression of AKT, PI3K, and mTOR proteins was also down-regulated in phlorizin-treated TNF-α-stimulated FLSs. Phlorizin protects against inflammation and reduces injury to synovial tissues in RA by modulating the AKT/PI3K/mTOR pathway.

A bioactive and biodegradable vitamin C stearate-based injectable hydrogel alleviates experimental inflammatory arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory joint disorder affecting nearly 1% of the global population. In RA, synovial joints are infiltrated by inflammatory mediators and enzymes, leading to articular cartilage deterioration, joint damage, and bone erosion. Herein, the 9-aminoacridine-6-O-stearoyl-L-ascorbic acid hydrogel (9AA-SAA hydrogel) was formulated by the heat-cool method and further characterized for surface charge, surface morphology, rheology, and cytocompatibility. Furthermore, we evaluated the therapeutic efficacy of the 9AA-SAA hydrogel, an enzyme-responsive drug delivery system with on-and-off switching capabilities based on disease severity against collagen-induced experimental arthritis in Wistar rats. The anti-inflammatory action of the US FDA-approved drug 9-aminoacridine (9AA) was revealed which acted through nuclear receptor subfamily 4 group A member 1 (NR4A1), an anti-inflammatory orphan nuclear receptor that inhibits nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Furthermore, we have explored the role of ascorbic acid, an active moiety of 6-O-stearoyl-L-ascorbic acid (SAA), in promoting the production of collagen production through ten-eleven translocation-2 (TET2) upregulation. Targeting through NR4A1 and TET2 could be the probable mechanism for the treatment of experimental arthritis. The combination of 9AA and ascorbic acid demonstrated enhanced therapeutic efficacy in the 9AA-SAA hydrogel, significantly reducing the severity of experimental arthritis. This approach, in contrast to existing treatments with limited effectiveness, presents a promising and more effective strategy for RA treatment by mitigating inflammation in experimental arthritis.